Synthesis of some 3-(1-azabicyclo[2.2.2]octyl) 3-amino-2-hydroxy-2-phenylpropionates: profile of antimuscarinic efficacy and selectivity.
A series of 3-quinuclidinyl atrolactate [3-(1-azabicyclo[2.2.2]octyl) 2-hydroxy-2-phenylpropionate, QNA] derivatives in which the methyl group of the parent is substituted with a tertiary amino substituent was prepared and tested for antimuscarinic activity. In general, potency was markedly decreased, although the morpholinyl and thiomorpholinyl derivatives retained significant activity. These compounds were also examined for muscarinic receptor subtype selectivity. Their subtype selectivities were comparable to that of (R,R)-QNA. The results of this investigation suggest possible differences in the accessory binding sites of the proteinaceous receptor subtypes.
Audia
V H
VH
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224-2788.
McPherson
D W
DW
Weitzberg
M
M
Rzeszotarski
W J
WJ
Sturm
B
B
Kachur
J F
JF
Abreu
M
M
Kaiser
C
C
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D007773:Lactates / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010276:Parasympatholytics; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000494:pharmacology*; D011812:Quinuclidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D007773:Lactates; D010276:Parasympatholytics; D010666:Phenylpropionates; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate; D002217:Carbachol